| In mammals, insulin signaling affects many cell functions, ranging from glucose transport to mitogenesis. The pathway is evolutionarily conserved, with component molecules identified in Caenorhabditis elegans and Drosophila melanogaster. However, some research suggests important differences between the mammalian and insect insulin signaling pathways. Unlike mammalian insulin receptors, the Drosophila insulin receptor (dIR) has a C-terminal extension with motifs to bind downstream molecules. The presence of these motifs implied that dIR might not require an insulin receptor substrate (IRS) adaptor molecule for interactions with downstream effectors. Additionally, despite the suggestion of insulin-like activity in Drosophila, no insulin genes had been identified. Subsequently, I have cloned and characterized an IRS as well as insulin genes in Drosophila.;A cDNA encoding Drosophila IRS (dIRS) was isolated, the chromosomal location of the gene determined, and its expression in a Drosophila cell line confirmed. In addition to sequence similarities, many functional similarities exist between dIRS and mammalian IRS proteins. First, MRS interacts with the dIR through its phosphotyrosine binding domain. Second, in response to insulin, a conserved motif in dIR phosphorylates MRS. Interestingly, additional copies of this motif, unique to the dIR extension, were required for stable association of dIRS with MR. Third, phosphorylation of MRS causes association with molecules in downstream signaling pathways, such as phosphatidylinositol 3-kinase. These data support the hypothesis that dIRS functions directly downstream from the IR in Drosophila.;Through analysis of the partially completed Drosophila genome, five insulin genes were identified. These genes are similar to mammalian insulin in their protein organization as well as the conservation of six cysteine residues required for disulfide bond formation. The putative coding regions of these molecules were isolated from cDNA libraries, confirming that four of the five genes are transcribed. Like the insulin genes found in C. elegans, there are developmental differences in expression among the Drosophila genes encoding insulin.;The existence of an IRS as well as insulin-like genes in Drosophila emphasizes the similarities between the insulin action pathways of insects and mammals. This suggests that biochemical, developmental, and genetic studies in Drosophila may provide novel insights into the mammalian insulin pathway. |
